(19) TZZ¥__Z¥_T (11) EP 3 110 843 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 31/4745 (2006.01) A61K 39/395 (2006.01) 11.09.2019 Bulletin 2019/37 A61K 31/573 (2006.01) A61K 31/65 (2006.01) A61K 31/675 (2006.01) A61P 35/00 (2006.01) (2006.01) (21) Application number: 15755187.0 A61P 35/02 (22) Date of filing: 25.02.2015 (86) International application number: PCT/US2015/017420 (87) International publication number: WO 2015/130728 (03.09.2015 Gazette 2015/35) (54) COMBINATION THERAPIES WITH ANTI-CD38 ANTIBODIES KOMBINATIONSTHERAPIEN MIT ANTI-CD38-ANTIKÖRPERN POLYTHÉRAPIES AVEC DES ANTICORPS ANTI-CD38 (84) Designated Contracting States: US-A1- 2012 231 008 US-A1- 2013 109 593 AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO • SATHISH GOPALAKRISHNAN ET AL: PL PT RO RS SE SI SK SM TR "Daratumumabimproves the anti-myeloma effect Designated Extension States: of newly emerging multidrug therapies", BLOOD BA ME AND LYMPHATIC CANCER: TARGETS AND THERAPY, DOVE MEDICAL PRESS LTD, GB, vol. (30) Priority: 28.02.2014 US 201461946002 P 2013, no. 3, 18 April 2013 (2013-04-18), pages 02.06.2014 US 201462006386 P 19-24, XP002735277, ISSN: 1179-9889, DOI: 10.2147/BLCTT.S29567 (43) Date of publication of application: • RICHARDSON P ET AL: "Daratumumab. 04.01.2017 Bulletin 2017/01 Anti-CD38 monoclonal antibody, treatment of multiple myeloma", DRUGS OF THE FUTURE, (73) Proprietor: Janssen Biotech, Inc. PROUSSCIENCE, ES, vol. 38, no. 8, 1 August 2013 Horsham, PA 19044 (US) (2013-08-01) , pages 545-554, XP002735278, ISSN: 0377-8282, DOI: (72) Inventor: DOSHI, Parul 10.1358/DOF.2013.038.08.2025424 [retrieved on Spring House, 2014-12-07] Pennsylvania 19477 (US) • M. DE WEERS ET AL: "Daratumumab, a Novel Therapeutic Human CD38 Monoclonal Antibody, (74) Representative: Carpmaels & Ransford LLP Induces Killing of Multiple Myeloma and Other One Southampton Row Hematological Tumors", THE JOURNAL OF London WC1B 5HA (GB) IMMUNOLOGY, vol. 186, no. 3, 27 December 2010 (2010-12-27), pages 1840-1848, XP55210884, (56) References cited: ISSN: 0022-1767, DOI: 10.4049/jimmunol.1003032 EP-A2- 2 567 976 WO-A1-01/97844 • Anonymous: "Multiple Daratumumab Abstracts WO-A1-2009/062054 WO-A1-2009/118142 to be Presented at EHA | Arraydiagnostica", , 22 WO-A1-2011/154453 WO-A1-2014/178820 May 2014 (2014-05-22), XP55382869, Retrieved WO-A2-2008/150530 US-A1- 2007 148 178 from the Internet: US-A1- 2009 076 249 US-A1- 2011 300 157 URL:http://www.arraydiagnostica.com/multip le-daratumumab-abstracts-to-be-presented-a t-eha/ [retrieved on 2017-06-20] Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 3 110 843 B1 Printed by Jouve, 75001 PARIS (FR) (Cont. next page) EP 3 110 843 B1 • DOSHI P ET AL: "Daratumumab treatment in combination with CHOP or R?CHOP results in the inhibition or regression of tumors in preclinical models of non?hodgkins lymphoma", HAEMATOLOGICA, THE HEMATOLOGY JOURNAL : OFFICIAL ORGAN OF THE EUROPEAN HEMATOLOGY ASSOCIATION, FONDAZIONE FERRATA STORTI, IT, vol. 99, no. Suppl.1, June 2014 (2014-06), page 138, XP009194729, ISSN: 0390-6078 2 EP 3 110 843 B1 Description FIELD OF THE INVENTION 5 [0001] The present invention relates to combination therapies with anti-CD38 antibodies. BACKGROUND OF THE INVENTION [0002] CD38 is a multifunctional protein having function in receptor-mediated adhesion and signaling as well as me- 10 diating calcium mobilization via its ecto-enzymatic activity, catalyzing formation of cyclic ADP-ribose (cADPR) and ADPR. CD38 mediates cytokine secretion and activation and proliferation of lymphocytes (Funaro et al., J Immunolog 145:2390-6, 1990; Terhorst et al., Cell 771-80, 1981; Guse et al., Nature 398:70-3, 1999). CD38, via its NAD glycohy- drolase activity, also regulates extracellular NAD+ levels, which have been implicated in modulating the regulatory T- cell compartment (Adriouch et al., 14:1284-92, 2012; Chiarugi et al., Nature Reviews 12:741-52, 2012). In addition to 15 signaling via Ca2+, CD38 signaling occurs via cross-talk with antigen-receptor complexes on T- and B-cells or other types of receptor complexes, e.g., MHC molecules, involving CD38 in several cellular responses, but also in switching and secretion of IgG1. [0003] CD38 is a type II transmembrane glycoprotein expressed on hemopoietic cells such as medullary thymocytes, activated T- and B-cells, resting NK cells and monocytes, lymph node germinal center lymphoblasts, plasma B cells, 20 intrafollicular cells and dendritic cells. A portion of normal bone marrow cells, particular precursor cells as well as unbilic al cord cells are CD38-positive. In addition to lymphoid precursor cells, CD38 is expressed on erythrocytes and on platelets, and expression is also found in some solid tissues such as gut, brain, prostate, bone, and pancreas. Mature resting T- and B-cells express limited to no surface CD38. [0004] CD38 is also expressed in a variety of malignant hematological diseases, including multiple myeloma, leukemias 25 and lymphomas, such as B-cell chronic lymphocytic leukemia, T- and B-cell acute lymphocytic leukemia, Waldenstrom macroglobulinemia, primary systemic amyloidosis, mantle-cell lymphoma, pro-lymphocytic/myelocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, follicular lymphoma, Burkitt’s lymphoma, large granular lymphocytic (LGL) leukemia, NK-cell leukemia and plasma-cell leukemia. Expression of CD38 has been described on epithelial/endothelial cells of different origin, including glandular epithelium in prostate, islet cells in pancreas, ductal epithelium in glands, 30 including parotid gland, bronchial epithelial cells, cells in testis and ovary and tumor epithelium in colorectal adenocar- cinoma. Other diseases, where CD38 expression may be involved, include, e.g., broncho-epithelial carcinomas of the lung, breast cancer (evolving from malignant proliferation of epithelial lining in ducts and lobules of the breast), pancreatic tumors evolving from the β-cells (insulinomas), tumors evolving from epithelium in the gut (e.g., adenocarcinoma and squamous cell carcinoma), carcinoma in the prostate gland, and seminomas in testis and ovarian cancers. In the central 35 nervous system, neuroblastomas express CD38. [0005] The potential use of anti-CD38 antibodies in the treatment of cancers has previously been described (Gopalakrishnan et. al., Blood And Lymphatic Cancer: Targets And Therapy, 2013(3):19-24, 2013; Richardson et. al., Drugs Of The Future, 38(8):545-554, 2013; De Weers et. al, The Journal Of Immunology, 186(3) 1840-1848, 2011; U.S. Pat. Publ. No 2009/076249). 40 [0006] B-cell malignancies may arise in all lymphoid tissues where B-cells are normally being produced. Most patients with B-cell malignancies are initially diagnosed with disease involving bone marrow or lymph nodes. In the case of bone marrow involvement, the transformed B cells frequently circulate through the blood and become widely disseminated throughout peripheral lymphoid tissues. However, B-cell malignancies may also arise in some nonlymphoid tissues such as the thyroid, gastrointestinal tract, salivary glands and conjunctiva. 45 [0007] Well known B-cell malignancies include B-cell chronic lymphocytic leukemia, mantle cell lymphoma, Burkitt lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, multiple myeloma, Hodgkin’s lymphoma, hairy cell leuke- mia, primary effusion lymphoma and AIDS-related Non-Hodgkin’s Lymphoma (NHL). B-cell malignancies comprise more than 85% of diagnosed lymphomas. [0008] NHL is a broad classification of lymphomas originating from the lymphatic system when lymphocytes (B-cells 50 or T-cells) become malignant and proliferate uncontrollably to form a tumor mass. In total, NHL encompasses around 30 different subtypes of lymphoma with a range of phenotypes and prognoses. It is projected that the incidence of NHL will reach over 140,000 in the major market countries by 2019. [0009] Diffuse Large B-cell Lymphoma (DLBCL) is an aggressive most common subtype of NHL, accounting for 30-40% of lymphoid malignancy, and encompasses a biologically and clinically diverse set of diseases. Gene expression 55 profiling studies suggest that DLBCL can be separated into two groups on the basis of gene expression profiles; these groups are known as germinal center B-cell like (GCB) and activated B-cell-like (ABC) lymphomas. [0010] The standard of care for treatment of DLBCL is commonly called CHOP, a combination of cyclophosphamide, hydroxydaunorubicin (doxorubicin), vincristine and prednisone, or R-CHOP, a combination of anti-CD20 antibody ritux- 3 EP 3 110 843 B1 imab and CHOP. In addition, following remission, hematopoietic stem cell transplantation may be considered. The components of CHOP have previously been described in the art (Intl. Pat. Publ. Nos. WO 2001/097844, WO 2009/062054 and WO 2009/118142) [0011] Despite the current treatment options, the survival rates within high risk groups of aggressive NHL can be as 5 low as 30% over 5 years. Therefore, there is a need for effective treatments and combination treatments for NHL and B-cell malignancies. SUMMARY OF THE INVENTION 10 [0012] The invention provides an anti-CD38 antibody, for use in treatment of a subject having a CD38-positive hema- tological malignancy, wherein the anti-CD38 antibody is administered in combination with cyclophosphamide, doxoru- bicin, vincristine and prednisone (CHOP), wherein the anti-CD38 antibody: i.induces in vitro killing of CD38-expressingcells by antibody-dependent cell-mediated cytotoxicity(ADCC), antibody- 15 dependent cellular phagocytosis (ADCP), complement dependent cytotoxicity (CDC), apoptosis, or in vitro modu- lation of CD38 enzymatic activity; ii.